Urinary tract infection (UTI) affects 2.6% to 3.4% of children in the US annually, and accounts for more than 1 million office visits, 94,000 hospital outpatient visits and (40,000 admissions each year. The economic burden just for UTI hospitalizations totals $180 million. Vesicoureteral reflux (VUR) occurs in 35% of children with UTI, increasing the risk of infection and long-term sequelae. This proposal aims to evaluate the effectiveness of management strategies in improving outcomes of children with VUR. Continuous antimicrobial prophylaxis has become accepted therapy for children with VUR, although scant evidence is available to support this practice. Similarly, the role of subureteral endoscopic surgery has not been properly evaluated. Recent changes in practice underscore the importance of determining the efficacy of prophylactic antimicrobials. These include: 1) earlier diagnosis and treatment of UTIs resulting in reduced renal scarring, 2) parental awareness of increased antimicrobial resistance and willingness to follow a "watchful waiting" path;and 3) prenatal identification of functional and anatomical obstructions of the urinary tract with widespread use of ultrasound (separating these children from those diagnosed with VUR following an index UTI). This proposal consists of a multicenter, randomized, placebo-controlled, double-blind clinical trial to evaluate the efficacy of prophylactic antimicrobials in preventing renal scarring and reinfections in children aged 2-36 months old with VUR. Children with Grades l-lll VUR will be randomized to receive prophylactic antimicrobial therapy or placebo;a third arm could readily be added to evaluate the efficacy of subureteral endoscopic surgery. Children with grades IV-V VUR will receive antimicrobial prophylaxis because they have the highest risk of developing renal scarring. Children will be recruited from 1) an Acute Care Pathway and 2) a Referral Care Pathway to enhance generalizability of study findings. Children's Hospital of Pittsburgh is in a unique position to participate in this cooperative agreement as a pediatric nephrology/urology Clinical Treatment Center. Distinguishing features of our setting include 1) an interdisciplinary team of experienced clinical investigators representing the various subspecialties, which has 2) a strong record of clinical research accomplishments in pediatric UTI and VUR, and 3) extensive expertise in research methods and in recruiting and retaining a large number of children in clinical trials